Just four weeks after returning to the field, San Francisco 49ers running back Christian McCaffrey is out again.

The 49ers head coach told reporters Monday that McCaffrey suffered a posterior cruciate ligament injury in Sunday’s 35-10 loss to the Buffalo Bills and will be placed on injured reserve. McCaffrey’s recovery is expected to take six weeks, meaning the remainder of his season is in jeopardy.

Additionally, Jordan Mason — who took over as RB1 after McCaffrey left Sunday night’s game — is going on IR after suffering a high ankle sprain.

During the second quarter of Sunday night’s game, McCaffrey suddenly began a run after suffering the non-contact injury. A moment later he walked into the blue medical tent and then walked back to the locker room under his own power.

The 49ers initially considered McCaffrey’s return questionable, but ruled him out before the start of the second half. After the game, Kyle Shanahan told reporters that McCaffrey’s PCL injury was “potentially” season-ending, but gave no further details.

With both McCaffrey and Mason out, rookie Isaac Guerendo will likely step in as San Francisco’s running back.

McCaffrey made his season debut in early November after missing the first eight games of the season due to Achilles tendonitis and calf strains. Shortly after McCaffrey went on IR before Week 2, he flew to Germany to receive treatment from a specialist.

McCaffrey has played in four games since returning, recording 50 carries for 202 yards and 15 receptions for 146 yards. He was the leading rusher in his first three games with San Francisco.

After Sunday’s loss, the 49ers fell to a record of 5-7 and are at the bottom of the NFC West. McCaffrey’s return last month was a huge boon for the team, but San Francisco has a number of other problems that the reigning Offensive Player of the Year couldn’t solve alone. Injuries also affected the team’s performance, with several key players missing this season.